Synthesis of cis-beta-bergamotene



United States Patent 3,481,998 SYNTHESIS OF CIS-BETA-BERGAMOTENE ThomasW. Gibson, Cincinnati, and William F. Erman,

Springfield Township, Hamilton County, Ohio, assignors to The Procter &Gamble Company, Cincinnati, Ohio, a corporation of Ohio No Drawing.Filed Dec. 16, 1966, Ser. No. 602,132 Int. Cl. C07d 7/18; C07c 13/28 US.Cl. 260-6755 3 Claims ABSTRACT OF THE DISCLOSURE SCOPE OF THE INVENTIONThis invention relates to the synthesis of cis-p-bergamotene andtherefore represents the first total synthesis of a ar-substitutedpinene sesquiterpene. More specifically, a multi-step process startingwith readily preparable 2-carboalkoxymethylnopinol, through theformation of several novel intermediate compounds, and resultingultimately in the formation of cis-fi-bergamotene has been discovered. Akey step in this process and an important feature of this invention isthe cyclization of certain nopinol compounds to form noveloxatricyclo[5.2.0.0 nonyl compounds.

fl-Bergamotene is a known compound, having been isolated from Valerianroot oil by Kulkarni et al. as reported in Tetrahedron Letters, 8, 505(1963). A comparison of the nuclear magnetic resonance spectrum of thefl-bergamotene prepared by the present invention (Example I, infra) withthat of naturally occurring fl-bergamotene as reported by Kulkarni etal. in Tetrahedron, 22, 1917 (1966) revealed the non-identity of thesecompounds. This non-identity is believed to reside in the cis-transstereo configuration of said compounds. It is also to be noted that thecis structure for p-bergamotene (as shown by compound 10, Figure I,infra) has been assigned to naturally occurring fi-bergamotene in theabove-cited Tetrahedron (1966) reference. However, due to theunambiguous nature of the synthesis of the present invention, it isconcluded that the product obtained hereby is cis-B-bergamotene, andtherefore the naturally occurring isomer is believed to betrans-fl-bergamotene (as shown by compound 11 Figure I, infra).

In any event, cis-fi-bergamotene prepared by the process of thisinvention has a unique and desirable odor and thus has utility as anodorant or as a component of perfume compositions as discussed in detailhereinafter. In addition, the novel oxatricyclo[S.2.0.0 ]nonyl compoundsmentioned above also have utility based on their olfactory properties.Novel oxo derivatives of these oxatricyclo[5.2.0.0 ]nonyl compounds havealso been prepared as a part of this invention and these compoundslikewise have useful olfactory characteristics.

Accordingly, objects of this invention are: To provide a novel synthesisof cis-fi-bergamotene; to provide novel compounds useful asintermediates in said synthesis of cis-,B-bergamotene; to provide anovel cyclization reaction 3,481,998 Patented Dec. 2, 1969 lCC useful insaid synthesis of cis-fi-bergamotene; and to provide noveloxatricyclo[5.2.0.0 ]nonyl products of said cyclization reaction andderivatives thereof having useful olfactory characteristics. Furtherobjects of this invention relating to the perfume and detergent artswill be evident hereinafter.

SYNTHESIS OF CIS-fi-BERGAMOTENE The above-described and other objectsare achieved by a novel process for the synthesis of cis-B-bergamotene,which comprises:

(a) Cyclizing 2-carboalkoxymethylnopinol (1) preferably2-carboethoxymethylnopinol) to form alkyl-1-methyl-B-oxatricyclo[5.2.0.0 ]nonyl-2-acetate (2) (preferably alkyl isethyl);

.(b) Hydrolyzing the acetate (2) of step (a) to form1-methyl-3-oxatricyclo[5.2.0.0 ]nonyl-2-acetic acid (3);

(c) Decarboxylating and halogenating the acetic acid (3) of step (b) toform 1rnethyl-4-halomethyl-3-oxatricyclo[5.2.0.0 ]nonane (4) (preferablyhalo is chloro);

(d) Cleaving the nonane (4) of step (c) to form 9-hydroxy-B-pinene .(5)

(e) Tosylating the pinene (5) of step (d) to form 9-toluenesulfonyloxy-fi-pinene (6);

(f) Displacing the pinene (6) of step (e) with sodium iodide to form9-iodo-fi-pinene (7 (g) Displacing the pinene (7) of step (f) withlithium acetylide to form Q-ethynyl-fi-pinene (8);

(h) Hydroborating the pinene (8) of step (g) with disiamylborane to form9-(B-pinyl)-acetaldehyde (9); and

(i) Reacting the aldehyde (9) of step (h) with triphenylisopropylidenephosphorane to form cis-,B-bergamotene (10).

The above-identified process for the synthesis of cis-13- bergamotenecomprising steps (a) through (i) is illustrated in Figure I and isdescribed in more detail in Example I, infra. Step (a) is discussed indetail under The Cyclization Reaction, infra. Respective steps (b)through (i) each involve individual reactions whose conditions are knownin the art. References wherein these conditions are disclosed aresummarized in Table 1. This table also shows preferred temperatureconditions for each step.

TABLE 1 Preferred Temperature Conditions Narrow Range Broad (HighlyRange, Preferred), Step 0. 0. Reference (b) 20-100 25-50 N. A. Abrahamet al., Compt. rend.,

248, 2880 (1959). (c) 50-100 -85 .T. Kochi, J. Org. Chem. 30, 3265(1965). (d) 70-125 -90 R. C. Blume et al., J. Org. Chem., 30,

1553 (1965). (e). -5-12 0-10 71;.nsell et al., J. Chem. 800., 1788 (i)40-100 55-65 M.1]g57Anse11 et al., J. Chem. Soc. 1788 0-35 10-30Copending US. Patent application of Erman et al., Ser. No. 549,812,filed May 13, 1966. (h) 0-40 0-10 H. C. Brown et al., J. Am. Chem. Soc.,

83, 3834 (1961). (i) 50-100 60-70 U. H. M. Fagerlund et al., J. Amer.

Chem. Soc., 79, 6473 (1961).

R=a1kyl of 1-6 carbon atoms, preferably ethyl Step Y KH step (91%2-carboethoxymethylnopinol (1), the preferred starting material in thisinventions synthesis of cis-p-bergamotenc can be prepared in two stepsstarting with readily available p-pinene.

First, B-pinene is converted by ozonolysis to nopinone according to themethod of Meinwald and Gassman as reported in J. Am. Chem. Soc., 82,5445 (1960) Nopinone is then reacted with ethylbromoacetate and zinc toform 2-carboethoxymethylnopinol (1) according to the method of Wallachas reported in Ann., 357, 49 (1907). Substitution of otheralkylbromoacetates results in the formation of corresponding2-carboalkoxymethylnopinols which can also be used as the startingmaterial in this inventions synthesis when alky contains from 1 to about6 carbon atoms.

Cis-fl-bergamotene has a unique and desirable Odor described aslemon-lime with a woody, slightly cam- Step (h) Formula 1.

X=L Br or cl,

- preferably 01.

cor!

Ii CH X phoraceous background with a touch of minty sweetness. Thiscompound can be used as an odorant per se or as a component of perfumecompositions for ultimate use in products such as soaps, detergents,deodorants and the like. Perfume compositions, preferably of the spicecologne type, containing odoriferously effective amounts, e.g., 0.0001%to 60%, preferably 1% to 20%, of cis-p-bergamotenc, are desirable anduseful as illustrated in more detail in Examples VI, XI, and XII, infra.

NOVEL INTERMEDIATE COMPOUNDS IN THE SYNTHESIS OF CIS-fi-BERGAMOTENE Allof the compounds 2 through 9 prepared as intermediates in thisinventions synthesis of cis-B-bergamotene are novel compositions ofmatter and can be generically defined as compounds of the generalformula selected from the group consisting of and Formula I I wherein: Ris selected from the group consisting of -CH CO R and CH X; R isselected from the group consisting of H (3) and R (2); R is an alkylradical of from 1 to about 6 carbon atoms; X is selected from the groupconsisting of I, Br and Cl (4); and M is selected from the groupconsisting of CH OH (5), -CH OSO C H (6), CH I (7), CH2C'ECH (8), and CHCH CH0 (9).

Many of the above-defined compounds of Formula I and Formula II havedesirable odor properties and thus have utility in the perfume arts.However, all of these compounds have primary utility as intermediates inthe synthesis of cis-[i-bergamotene.

THE CYCLIZATION REACTION The cyclization of 1 to form 2 described aboveunder The Synthesis of cis-B-Bergamotene (step (a)) is but oneembodiment of a more broadly applicable novel cyclization reaction,which comprises: reacting a nopinol compound of the general formulaFormula ll rrr with a compound selected from the group consisting ofacetates and oxides of lead, silver and mercury in the presence ofmolecular halogen selected from the group consisting of bromine,chlorine and iodine, to form a 3-oxatricyclo[5.2.0.0 ]nonane compound ofthe general formula Formula 17:

III

wherein in both of the above general Formulas III and IV, R is selectedfrom the group consisting of H, R and CH 'CO R and R and R are each analkyl radical of from 1 to about 6 carbon atoms, preferably of from 1 toabout 2 carbon atoms.

When R is CH CO R in Formulas III and IV, the cyclization reactionrepresents step (a) of the synthesis of cis-fi-bergamotene. Accordingly,the preparation of the Formula III compound for R =CH CO RZ-carboalkoxymethylnopinol (1), and the use of the corresponding FormulaIV product, alkyl-l-methyl-3-oxatricyclo [5.2.0.0 ]nonyl-Z-acetate (2),as an intermediate in the synthesis of cis-B-bergamotene, step (b), havebeen described hereinbefore.

The preparation of Formula III compounds for R R (alkyl radical of from1 to about 6 carbon atoms, i.e., these compounds are alkylnopinols) canbe accomplished by the addition of alkyllithium to nopinone (nopinone isprepared by ozonolysis of p-pinene, supra) in the same manner asreported by Huckel and Gelchscheimer in Ann., 625, 12 (1959).

The preparation of the Formula III compound for R H, i.e., nopinol, canbe accomplished by lithium aluminum hydride reduction of nopinoneaccording to the method of Winstein and Holness as reported in J. Am.Chem. Soc., 77, 3054 (1955).

Examples of suitable acetates or oxides of lead, silver or mercury forthe cyclization reaction are mercuric oxide, lead tetraacetate, silveracetate, silver oxide and lead oxide (PbO or Pb O Br is the molecularhalogen preferably used with mercuric oxide, silver acetate and silveroxide while I is preferably used with lead tetraacetate. Either Br or 1can be used equally well with lead oxide. When I is used as themolecular halogen, it is desirable to irradiate the reactants withvisible (tungsten) light during the cyclization reaction.

The cyclization reaction is preferably carried out in the presence of aninert solvent. Suitable inert solvents include: saturated hydrocarbons,preferably of from about 5 to about 12 carbon atoms, e.g., pentane,hexane, cyclohexane, dodecane and the like; aromatic hydrocarbons,preferably of from about 6 to about 9 carbon atoms, e.g., benzene ortoluene; and halogenated hydrocarbons, preferably of from about 1 toabout 10 carbon atoms, e.g., chloroform, ethylene dichloride and thelike.

For the cyclization reaction, the concentration of the Formula IIIstarting material in the solvent should be within the range of fromabout 0.01 M to about 1.0 M, preferably from about 0.1 M to about 0.5 M.At least one mole of oxide or acetate and at least one mole of molecularhalogen should be present in the reaction system per mole of Formula IIIstarting material. Preferably, the mole ratio of oxide or acetate to theFormula III material as well as the mole ratio of molecular halogen toFormula III material is within the range of from about 1.1:1 to about5:1.

The temperature of the cyclization reaction can be within the range offrom 0 C. to about 150 C., preferably, from about 10 C. to about C. Morepreferably, the reaction is carried out at reflux conditions, i.e., at atemperature corresponding to the boiling point of the solvent used,e.g., 36 C. when pentane is the solvent. Further details on thecyclization reaction are found in Example I (step (a)), Example II andExample III, infra.

NOVEL PRODUCTS OF THE CYCLIZATION REAC- TION AND NOVEL DERIVATIVESTHEREOF The Formula IV cyclization products for R =R (alkyl radical offrom 1 to about 6 carbon atoms), i.e., 1 methyl 4alkyl-3-oxatricyclo[5.2.0.0 ]nonane compounds, have fenchone-eucalyptolodors and these novel compounds therefore have utility as components ofperfume compositions. These compounds can be oxidized by the addition ofCrO in the presence of acetic anhydride and acetic acid to form novel1-methyl-4-alkyl-2-oxo-3- oxatricyclo[5.2.0.0 ]nonane compounds of thegeneral formula Formula L wherein R is the same as in Formula IV.

The Formula V compounds described above have a unique odor defined aspungent, pithy-stemmy with a sweet woody-animal background.

Formula IV and Formula V compounds can be used individually, or inadmixture with each other, as odorants per se or as components ofperfume compositions for ultimate use in products such as soaps,detergents, deodorants and the like. Perfume compositions containingodoriferously effective amounts, e.g., 0.001% to 60%, preferably 1% to40%, of Formula IV and/or Formula V compounds, are desirable and useful.Woody-lavender type perfume compositions are particularly suited for theincorporation of Formula IV and/or Formula V compounds therein. Furtherdetails on the perfume utility of Formula IV and Formula V compounds arefound in Examples VII, VIII, XI and XH, infra. A preferred Formula IVand/ or Formula V compound is obtained when R =methyl.

The Formula IV cyclization product for R =H, i.e.,1methyl-3-oxatricyclo[5.2.0.0 ]nonane, has an odor defined asclean-camphor and this novel compound therefore has utility as acomponent of perfume compositions. This compound can be oxidized by theaddition of CrO in the presence of acetic anhydride and acetic acid toform the novel compound 1-methyl2-oxo-3-oxatricyclo[5.2.0.0 nonane(Formula V structure, R =H). This product has an odor defined as woody,tobacco, slightly butyric and can be used as an odorant per se or as acomponent of perfume compositions for ultimate use in products such assoaps, detergents, deodorants and the like. Perfume compositions,preferably of the Woody-lavender type, containing odoriferouslyeffective amounts, e.g., 0.000l% to 60%, preferably 1% to 40%, of1-methyl-3-oxatricyclo- [5.2.0.0 ]nonane and/or1-methy1-2-oxo-3-oxatricyclo- [5.2.0.0 ]nonane are desirable and useful.See Examples IX, X, XI and XII, infra.

An alternative method of preparing 1-methyl-2-oxo-3- oxatricyclo[5.2.0.0]nonane starting initially with nopinone is disclosed in the copendingUS. patent application of Thomas W. Gibson, Ser. No. 602,141, filedconcurrently herewith.

Therefore, in summary, this invention provides novel compounds of thegeneral formula selected from the group consisting of wherein: Z isselected from the group consisting of CH C R CH CO H, CH X, H and R Y isselected from the group consisting of H and R, R and R are each an alkylradical of from 1 to about 6, preferably of from 1 to about 2, carbonatoms, X is selected from the group consisting of I, Br, and Cl,preferably Cl; and M is selected from the group consisting of CH OH,'CH2OSO2C'1H7, CH2I, and CH CH CHO.

In the following examples, N.M.R. spectra were obtained on a VarianAssociates HA-100 spectrometer. Gas chromatographic analyses wereperformed on an Aerograph A-90P instrument using Carbowax 20M packedcolumns in the range of 60200 C. Microanalyses were obtained on aPerkin-Elmer Infracord Spectrometer, and ultraviolet spectra wereobtained from a Cary Model 14 spectrometer. All percentages and ratiosin the following examples, as well as in this specification and theappended claims are by weight unless indicated otherwise. Also in thefollowing examples, abbreviations and symbols are defined as indicated:EtOH=ethy1 alcohol; Ae=acetate; Ar=argon; DMSO=dimethyl sulfoxide;THF=tetrahydrofuran; room temperature=24-26 C.

Example 1.-Synthesis of cis-fl-bergamotene Step (a).To a mixture of 20.2g. of 2-carboethoxymethylnopinol (1, R=ethyl) and 33 g. yellow HgO in500 ml. pentane was added 22 g. Br During addition the pentane was keptat reflux (-36 C.) and a stream of Ar was passed through the system toremove HBr. After addition, reflux was continued for 1 hour, the mixturecooled, filtered, and dried over MgSO Removal of drying agent andsolvent gave 20.4 g. dark oil, which was filtered through 150 g. of A1 0twice to give 16.0 g. of ethyl-1-methyl-3-exatricyclo [5 2.0.0nonyl-2-acetate (2, R=ethyl) (80%), which appeared to be pure by gaschromatography. Purification was carried out by gas chromatographyfollowed by short-path distillation to give 2 with B.P. 88 (0.2 mm.), 111.4755, [a] +50.5 [2.04, EtOH], A 5.78, 9.711., and N.M.R. signals at 7-8.76

8 (3H, triplet, .T-=7.1 cps.), 8.74 (3H, singlet), 8.51 (1H, doublet,1:9.0 cps., C -endQ-H), 7.98.4 (6H), 7.75 (1H, quartet, J=9.0 and 4.5cps., C -exo-H), 7.44 (2H, singlet), 6.43 (2H, AB quartet, J=8.6 cps.,6=44.6 cps., C CH and 5.90 (2H, AB quartet, J=7.1 cps., 6=14.0 cps.,

Analysis.-Calculated for C H O C, 69.61; H, 8.99. Found: C, 69.65; H,8.99.

In this part of Example I, substantially equivalent results are obtainedin that 1 is cyclized to 2 (R=ethyl) when: the pentane solvent isreplaced on a volume basis by another inert solvent, e.g., a saturatedhydrocarbon of from about 5 to about 12 carbon atoms such as pentane,hexane, cyclohexane or dodecane, an aromatic hydrocarbon of from about 6to about 9 carbon atoms such as benzene or toluene, or a halogenatedhydrocarbon of from about 1 to about 10 carbon atoms such as chloroformor ethylene dichloride; and/or the Br is replaced on a mole basis by I;or C1 and/or the HgO is replaced on a mole basis by another acetate oroxide of lead, silver or mercury, e.g., lead tetraacetate, silveracetate, silver oxide or lead oxide.

Also in this part of Example I, substantially equivalent results areobtained in that the corresponding alkyl-1- methyl-B-oxatricyclo [52.0.0. nonyl-2-acetate is formed when the 2-carboethoxymethylnopinol isreplaced by another Z-carbo-alkoxymethylnopinol wherein the alkylradical contains from 1 to about 6 carbon atoms, e.g., methyl, propyl,isopropyl, butyl, pentyl, 3-methylpentyl, and hexyl.

Steps (b) and (c).--Hydr0lysis of 15.5 g. of 2 (R=ethyl) with KOH inaqueous methanol at 25 C. gave a quantitative yield of1-methy1-3-oxatricyclo- [5.2.0.0 ]nonyl-2-acetic acid (3). To a solutionof 12.43 g. of the acid 3 at room temperature in 250 ml. benzene wasadded 44 g. Pb(OAc) and the mixture stirred until homogeneous, when 4.31g. NaCl was added, the system evacuated repeatedly to afford an Aratmosphere, and then heated at C. overnight. As the reaction proceeded,CO was given off and the color became lighter as Pb+ salts wereprecipitated. The solution was decanted from the gummy salts, washedwith dilute I IClO saturated Na CO saturated NaCl, dried over MgSOfiltered, the benzene removed in vacuum, and the residue chromatographedon 50 g. A1 0 Elution with 10% ether in pentane gave 5.50 g. pure1-methy1-4-chloromethyl-3- oxatricyclo[5.2.0.0 ]nonane (4, X=Cl). Anadditional 0.834 g. was obtained on rechromatography of the latterfractions. Purification by gas chromatography gave 4 with RP. 65 (1.3mm.), 11 14969, [a] +46.2 [2.17, EtOH], 8 9.75 t, M.W. 186 (mass spec.),and N.M.R. signals at T 8.73 (3H, singlet), 8.52 1H, doublet, J=8.5cps.), 7.7 84 (7H), 6.47 (2H, singlet), and 6.35 (2H, AB quartet, 1:09,6:46 cps.).

Analysis.Calculated for C H CIO: C, 64.33; H, 8.09; Cl, 19.10. Found: C,64.32; H, 7.89; CI, 19.18.

In this part of Example I, substantially equivalent results are obtainedin that 3 is formed when 2 is replaced by anotheralkyl-1-methyl-3-oxatricyclo[5.2.0.0 nonyl-2-acetate wherein the alkylradical contains from 1 to about 6-carbon atoms, e.g., methyl, propyl,butyl, pentyl, and hexyl.

Also in this part of Example I, substantially equivalent results areobtained in that the corresponding l-methyl- 4-halomethyl 3oxatricyclo[5.2.0.0 ]nonane (4) is formed when the 4.31 g. of NaCl isreplaced by NaI or NaBr.

Step (d).To a solution of 14.4 g. of 1-methyl-4-chloromethyl-3-oxatricyclo[5.2.0.0 ]nonane (4) in 150 ml. dry monoglymewas added 4.6 g. sodium, and the solution refluxed overnight C.). Aftercooling, the excess sodium was decomposed by" the addition of methanol,the solution diluted with water and extracted thoroughly with ether. Theether solution was washed with water, dried over MgSO filtered andstripped. Distillation of the residue gave 5.6 g. (48%) pure 9-hydroxy-B-pinene B.P. 55 (0.5 mm.), [a] +44.4 [1.80, EtOH], k 2.90, 3.22, 6.07,9.8, and 1136 M.W. 152 (mass spec.), and N.M.R. signals at T 8.70 (3H,singlet), 8.59 (1H, doublet, 1:9.0 cps.), 7.3-8.3 (8H), 6.67 (2H, ABquartet, J=10.6, 6=18.6 cps.), and 5.40 (2H, broad singlet).

Analysis.-Calculated for C H O: C, 78,89; H, 10.59. Found: C, 78.23; H,10.27.

In this part of Example I, substantially equivalent results are obtainedin that 5 is formed when the l-methyl-4-chloromethyl-3-oxatricyclo[5.2.0.0 ]nonane is replaced by another 1methyl 4 halomethyl 3 oxatricyclo- [5.2.0.0 ]nonane, e.g., -iodomethylor -bromomethyl-.

Step (e).To a solution of 5.20 g. of 9-hydroxy-5- pinene (5) in 90 ml.dry pyridine at 0 was added 6.55 g. toluene-sulfonyl chloride(tosylate), and the solution put in a 0 refrigerator overnight. Themixture was poured onto ice, extracted with ether, the ether washed withdilute HCl, saturated NaHCO dried over MgSO,, filtered and stripped.Crystallization of the residue from ether-pentane gave 7.4237 g. pure9-toluene-sulfonyloxy- B-pipene (6) (71%) M.P. 115", 3.22, 6.10, 6.27,7.33, 8.51, 10.4 and 11.3;i, and N.M.R. signals at 1- 8.79 (3H,singlet), 8.61 (1H, doublet, J=9.2 cps.), 7.48.4 (7H), 7.60 (3H,singlet), 6.33 (2H, AB quartet, J=9.4, 6:26 cps.), 5.50 (2H, broad), and2.5 (4H).

Analysis.-Calculated for C H SO C, 66.65; H, 7.34; S, 10.44. Found: C,66.58; H, 7.27; S, 10.48.

Step (f).A solution of 4.20 g. of 6 and 5.60 g. of NaI in 50 ml. ofpurified acetone was refluxed for 18 hours (55 C.). After cooling in anice bath to C. and filtration of the sodium tosylate, the acetone wasremoved in vacuum and the oily residue taken up in ether. The ethersolution was washed with a dilute Na S O solution and dried over MgSODistillation of the residue after filtration and removal of ether gave3.20 g. (89%) of 9-iodo- 3-pinene (7), B.P. 66 (0.4 mm.), n 1.5625, [u]+76.8 [1.63, EtOHLk 6.08 and 11.37 and N.M.R. signals at 1- 8.65 (3H,singlet), 8.68 (1H, doublet, 1:9.5 cps.), 7.3-8.3 (7H), 7.04 (2H, ABquartet, 1:9.4, 8=16.5 cps.), and 5.35 (2H, broad).

Analysis.Calcu-lated for C H I: C, 45.84; H, 5.77; I, 48.39. Found: C,45.93; H, 5.84; I, 48.50.

Step (g) .A solution of 2.4748 g. of 7 and 1.72 g. of theethylene-diamine complex of lithium acetylide in 50 ml. DMSO was stirredat room temperature under Ar for hours. The solution was poured intowater, neutralized with NH Cl solution, and extracted with pentane. Thepentane solution was washed with saturated NaCl solution, dried over NaSO filtered and stripped. Short-path distillation of the residue gave1.0673 g. (71%), B.P. -50 (0.5 mm.), which showed two peaks on gaschromatography in the ratio of 4:1 (planimeter). Spectral data formaterial giving the minor peak suggested an internal isomer while themajor product was shown to be the desired product, 9-ethynyl-flpinene(8). Pure material showed n 1.4975,

[ larm-F [1.95, EtOH], x,,,,,,, 3.00, 3.22, 4.70, 6.08 and 11.37 M.W.160 (mass spec.), and N.M.R. signals at 'r 8.63 (3H, singlet), 8.57 (1H,doublet, 1:9.6 cps.), 7.48.3 (10H), and 5.40 (2H, broad doublet).

Analysis-Calculated for C H C, 89.94; H, 10.06. Found: C, 89.78; H,9.97.

Step (h).To a solution of 0.303 g. of the mixture of products obtainedin step (g) in 20 ml. THF, cooled in an ice bath (10 C.), was added 2.0ml. of 1 M disiamylborane by syringe. The solution was then stirred fourhours at room temperature, decomposed with 2 ml. of 3 N NaOH and 2 ml.of 30% H 0 poured into water, and the water solution extracted withpentane. The pentane extract was dissolved with water, dried over Na SOfiltered and stripped to give 0.320 g. crude product. Gas

chromatography analysis indicated the presence of a number of compounds,the major peak of which (-30%) was shown to be the desired product,9-(B- pinyl)-acetaldehyde (9). Material collected by gas chromatographyshowed B.P. 90-5 (0.6 mm.), Amax 3.23, 3.68, 5.76, 6.08 and 11.4 M.W.178 (mass spec.), and N.M.R. signals at 1- 8.81 (3H, singlet), 8.57 (1H,doublet, J=9.0 cps.), 7.48.4 (11H), 5.40 (2H, broad doublet), and 0.30(1H, triplet, J=1.5 cps.).

Analysis.--Calcu-lated for C H O: C, 80.85; H, 10.18. Found: C, 80.15;H, 10.13.

Step (i).Triphenylisopropylidenephosphorane was generated from 1.93 g.of triphenylisopropylphosphonium bromide in 50 ml. THF by the additionof one equivalent of butyl lithium. After two hours at room temperature,0.305 g. of 9 1 was added and the mixture heaetd to 60 1 As the crudeproduct described in step (11).

overnight. After cooling, the mixture was poured into water, extractedwith pentane, and the pentane washed with water, dried over MgSOfiltered and stripped to give 0.235 g. crude product. This material wasfiltered through 6 g. A1 0 to give 0.099 g. hydrocarbons, consisting of(+)-cis-fl-bergamotene (10) and 10% acetylenes. Purification gave(+)-cis-fi-bergamotene with B.P. (0.5 mm.), [u] |-40.2 [1.74, CHCl k3.22, 6.06, 11.43 and 11.95p, M.W. 204 (mass spec.), N.M.R. signals at 18.77 (3H, singlet), 8.59 (1H, doublet, J=9.5 cps.), 8.42 (3H, singlet),8.34 (3H, singlet), 7.4-8.3 (11H), 5.40 (2H, doublet), and 4.93 (1H,triplet, 1:8.0 cps.), and an odor characterized as lemon-lime with awoody, slightly camphoraceous background with a touch of mintysweetness.

Analysis.--Calculated for C H C, 88.16; H, 11.84. Found: C, 87.93; H,11.16.

As is evident from Example I, each of the products 2 through 9 hasutility as an intermediate in the synthesis of cis-p-bergamotene.

Example II.-Cyclization of alkylnopinol to form 1-methyl-4-alkyl-3-oxatricy-clo[5.2.0.0 l- ]nonane (Formula IV, R =R To asolution of 100.8 g. of methylnopinol (Formula III, R =R =methyl) in 1liter distilled pentane was added 200 g. yellow mercuric oxide. Themixture was heated to reflux (-36 C.) under N and 20.0 ml. bromine addeddropwise over about two hours. After an additional two hours reflux at-36 C., the mixture was cooled, filtered and dried over MgSO, and N21 COFiltration through 450 g. A1 0 followed by vacuum distillation gave 69.0g. of 1,4-dimethyl 3 oxatricyclo- [5.2.0.0 ]nonane, B.P. 64 (10.5 mm.),and 15 g. nopinone, for an 82% yield of pure product. Material purifiedby gas chromatography showed n 1.4702, [a] +51.7 [3.0, EtOH], stronginfrared absorption at 9.7 M.W. 152 (mass spec.), N.M.R. signals at 1-8.74 (6H, singlet), 7.88.7 (8H), and an AB quartet at 1- 6.40 (2H, J=9.0cps., 5/J=5.1), and an odor characterized as fenchone-eucalyptol.

Analysis.-Calculated for C H O: C, 78.89; H, 10.59. Found: C, 78.21; H,10.49.

In this example, substantially equivalent results are obtained in thatthe corresponding 1-methyl-4-alkyl-3-oxatryclo[5.2.0.0 ]nonane is formedwhen the methylnopinol is replaced by another alkylnopinol wherin thealkyl radical contains from 1 to about 6 carbon atoms, e.g., ethyl,propyl, isopropyl, butyl, pentyl, and hexyl.

Also in this example, substantially equivalent results are obtained inthat 1,4-dimethyl-3-oxatricyclo[5.2.0.0 nonane is formed when: thepentane is replaced on a volume basis by another inert solvent, e.g.,one of the solvents listed under step (a) of Example I, supra; and/orthe bromine is replaced on a mole basis by C1 or I and the reactionmixture is irradiated with a 500 Watt tungsten light; and/or themercuric oxide is replaced on a mole basis by another acetate or oxideof lead, silver or mercury, e.g., lead tetraacetate, silver acetate,silver oxide or lead oxide.

Example III-Oxidation of 1-methy1-4-alkyl-3-oxatricyclo[5.2.0.0 ]nonaneto form 1-methyl-4-alkyl-2- oxo-3-oxatricyclo[5.2.0.0 ]nonane Formula V)A solution of 4.093 g. of 1,4-dimethyl-3-oxatricyclo- [5.2.0.0 ]nonaneprepared as in Example II was heated to 100 in 30 ml. acetic anhydride,and a solution of 4.30 g. CrO in 100 ml. acetic acid and 10 ml. H O wasadded over 1.5 hours. After cooling and addition of 10 ml. ethanol todestroy excess oxidant the solution was poured onto crushed ice,extracted with ether, and the ether extract washed with saturated Na COsolution and dried over MgSO Distillation of the residue after removalof drying agent and solvent gave 1.047 g. nearly pure starting materialand 2.414 g. (72%) of 1,4-dimethyl-2-oxo-3- oxatricyclo[ 5.2.0.0]nonane. This product had B.P. 84 (1.2 mm.), [a] +58.8 [2.16, EtOH], 15.64 (CCl M.W. 166 (mass spec.), N.M.R. signals at -r 8.64 (3H,singlet), 8.55 (3H, singlet), 8.32 (1H, doublet, J=9.7 cps.), 8.10 (4H,singlet), and 7.5-7.8 (3H), and an odor characterized as pungent,pithy-stemmy with a sweet woody-animal background.

AnaIyszs.Calculated for C H O C, 72.26; H, 8.49. Found: C. 72.12; H,8.56.

In this example, substantially equivalent results are obtained in thatthe corresponding 1-methyl-4-alkyl-2- oxa-3-oxatricyclo[5.2.0.0 ]nonaneis formed when the 4-methyl radical in the starting material is replacedby another alkyl radical of from about 2 to about 6 carbon atoms, e.g.,ethyl, propyl, butyl, sec-butyl, pentyl, and hexyl.

Example IV.-Cyclization of nopinol to form 1-methyl-3-oxatricyclo[5.2.0.O ]nonane (Formula IV, R =H) A solution of 2.0 g.nopinol (Formula III, R =H) in 175 ml. distilled pentane was treatedwith 8.0 g. HgO and 0.8 ml. Br as described in Example II, followed by aone hour -36 C. reflux period. Workup as in Example II gave, ondistillation, 1.214 g. of pure 1-methyl-3-oxatricyclo[5.2.0.0 ]nonaneplus a higher boiling fraction of 0.467 g. containing 60% product and40% nopinone; yield 75%. The product showed B.P. 60 (9.0 mm), n 1.4828,[a] |82.5 [2.86, EtOH], )t 9.63 and 9.78,u. M.W. 138 (mass spec.),N.M.R. signals at -r 8.69 (3H, singlet), 8.48 (1H, doublet, 1:9.0 cps. CH); 7.8-8.4 (6H), 7.63 (1H, quartet, 1:5.6 cps., C -H), 6.39 (2H, ABquartet, J=8.8 cps., 6=47.0 cps., C H), 5.44 (1H, broad doublet, J=6.4cps.), and had an odor charac terized as clean camphor.

Analysis.Calculated for C H O: C, 78.21; H, 10.21. Found: C, 78.29; H,10.18.

In this example, substantially equivalent results are obtained in that1-methyl-3-oxatricyclo[5.2.0.0 ]nonane is formed when: the pentane isreplaced on a volume basis by another inert solvent, e.g., a saturatedhydrocarbon of from about to about 12 carbon atoms usch as pentane,hexane, cyclohexane or dodecane, an aromatic hydrocarbon of from about 6to about 9 carbon atoms such as benzene or toluene, or a halogenatedhydrocarbon of from about 1 to about carbon atoms such as chloro form orethylene dichloride; and/or the Br is replaced on a mole basis by I orC1 and/or the HgO is replaced on a mole basis by another acetate oroxide of lead, silver or mercury, e.g., lead tetraacetate, silveracetate, silver oxide or lead oxide.

Example V.Oxidation of 1-methyl-3-oxatricyclo[5.2.0. 0 ]nonane to forml-methyl-2-oxo-3-oxatricyclo[5.2. 0.0 ]nonaue (Formula V structure, R H)Oxidation of 9.9 g. of 1-methy1-3-oxatricyclo[5.2.0. 0 ]nonane wascarried out as described in Example III for 1.4-dimethyl-3-oxatricycle[5.2.0.0 ]nonane to give 12.5 g. crude product, which was hydrolyzedwith excess KOH in aqueous methanol for one hour on a steam bath at -70C. After removal of methanol in vacuum, extraction with ether gave 2.6g. neutral materials consisting of starting ether and nopinone. Theaqeuous phase was acidified with dilute HCl and extracted with ether andmethylene chloride to give, after drying and distillation, 3.3 g. (31%)pure 1-methyl-2-oxo-3-oxatricyclo [5.2.O.0 ]n0nane, B.P. 83-4 (0.7 mm.),[a] +129 [2.61, EtOH], A 5.64; M.W. 152 (mass spec.), and N .M.R.signals at 78.68 (3H, singlet, 8.30 (1H, doublet, J 9.6 cps.), 8.09 (4H,singlet), 7.67.8 (2H), 7.31 (1H, quartet), and 5.07 (1H, doublet, I 6.6cps.). This compound had an odor characterized as woody, tobacco,slightly butyric.

Analysis.Calculated for C H O C, 71.02; H, 7.95. Found: C, 70.71; H.7.99.

Example VI.-Perfume compositions utilizing cis-fl-bergamotene A perfumecomposition is prepared by intermixing the components shown below.

Component: Percent by weight Cis-fi-bergamotent 10.00 Bergamot 40.00Geranium Bourbon 25.00 Patchouli 5.00 Sandalwood E.I 5.00 NeroliBigarade 5.00 Cassia 5.00 Musk Ambrette 5.00

This perfume composition exhibits a highly desirable and useful spicecologne odor.

The components and proportions in the perfume composition of thisexample can be adjusted according to methods well known in the perfumeart to form a wide variety of perfume compositions containingodoriferously effective amounts of cis-p-bergamotene.

Example VII.-Perfume compositions utilizing l-methyl-4-alkyl-3-oxatricyclo [5 2.0.0 nonane compounds A perfume composition isprepared by intermixing the components shown below.

This perfume composition exhibits a highly desirable and useful woodylavender odor. A substantially identical perfume composition is obtainedwhen another l-methyl- 4-alkyl-3-oxatricyclo [5.2.0.0 ]nonane compound,wherein the alykyl radical contains from 2 to about 6 carbon atoms(e.g., ethyl, propyl, isopropyl, butyl, pentyl, and hexyl), issubstituted on a weight basis for the 1,4-dimethyl-3-oxatricyclo[5.2.O.0 ]nonane.

The components and proportions in the perfume composition of thisexample can be adjusted according to methods wel known in the perfumeart to form a wide variety of perfume compositions containingodoriferously effective amounts of the 1-methyl-4-a1kyl-3-oxatricyclo[5.2.0.0 ]nonane compounds of this invention.

13 Example VIII-Perfume compositions utilizing l-methyl-4-alkyl-2-oxo-3-oxatrieyclo[5.2.0.0 nonane compounds A perfumecomposition is prepared by intermixing the components shown below.

This perfume composition exhibits a highly desirable and useful woodylavender odor. A substantially identical perfume composition is obtainedwhen another l-methyl- 4-alkyl-2-0xo-3-0Xatricyclo[5.2.0.0 ]nnanecompound, wherein the alkyl radical contains from 2 to about 6 carbonatoms (e.g., ethyl, propyl, 25 isopropyl, butyl, and hexyl), issubstituted on a weight basis for the1,4-dimethyl-2-oxo-3-oxatricyclo[5.2.0.0 ]nonane.

The components and proportions in the perfume comly effective amounts ofthe 1-methyl-4-alkyl-2-oxo-3-oxaposition of this example can be adjustedaccording to methods well known in the perfume art to form a widevariety of perfume compositions containin odoriferously elfectiveamounts of the l-methyl-4-alkyl-2-oxo-3-oxatricyclo[5.2.0.0 ]nonanecompounds of this invention.

Example IX.-Perfume compositions utilizingl-methyl-S-oxatricyclo[5.2.0.0fl1nonane A perfume composition isprepared by intermixing the components shown below.

Component: Percent by weight l-methyl-S-oxatricyclo[5.2.0.0*- ]nonane1.00 Lemon 10.00 Bergamot 12.00 Lavender 30.00 Sandalwood 15.00Patchouli 9.00 Labdanum 4.00 Musk Ambrette 15.00 Rosemary 1.00

This perfume composition exhibits a highly desirable and usefulwoody-lavender odor.

The components and proportions in the perfume composition of thisexample can be adjusted according to methods well known in the perfumeart to form a wide variety of perfume compositions containingodoriferously effective amounts of 1-methyl-3-oxatricyclo [5.2.0.0

nonane.

Example X.Perfume compositions utilizing l-methyl- 2-oxo-3oxatricyclo[5.2.0.0 ]nonane A perfume composition is prepared byintermixing the components shown below.

This perfume composition exhibits a highly desirable and usefulwoody-lavender odor.

The components and proportions in the perfume composition of thisexample can be adjusted according to methods well known in the perfumeart to form a wide variety of perfume compositions containingodoriferously eliective amounts of l-methyl-2-oxo-3-oxatricyclo [5.2.0.0]nonane.

Example XI.-Detergent compositions A conventional heavy-duty builtdetergent having the following composition is prepared.

Component: Percent by weight Sodium dodecyl benzene sulfonate 20.00Sodium tripolyphosphate 50.00 Sodium silicate 6.00 Sodium sulfate 14.00Water 9.80 Perfume composition of Example VI containingcis-B-bergamotene 0.20 This detergent composition exhibits a desirablespice Example XH. -Detergent bar compositions A conventional householddetergent bar having the following composition is prepared.

Component: Percent by weight Sodium soap 75.00 Potassium soap (the totalsoap comprises a mixture of tallow soap and 20% coconut soap) 7.50 Water15 .00 Perfume composition of Example VI containing cis-fl-bergamotene2.50

This detergent bar composition exhibits a desirable spice cologne odor.When the perfume composition of either Example VII or VIII issubstituted on a weight basis for the perfume composition of Example VIherein, the detergent bar composition exhibits a desirable woodylavender odor. When the perfume composition of either Example IX or X issubstituted on a weight basis for the perfume composition of Example VIherein, the detergent bar composition exhibits a desirable woodylavenderodor.

Other detergent bars, e.g., those disclosed in U.S. Patents 2,215,539,2,295,594, 2,407,647 and 3,066,354, can be substituted herein withequally satisfactory results.

What is claimed is:

1. A process for the synthesis of cis-fl-bergamotene, which comprises:

(a) eyclizing 2-carboalkoxymethylnopinol to form alkyl-I-methyl3-oxatricyclo[5.2.0.0 ]nonyl-2-acetate;

(b) hydrolyzing the acetate of step (a) to form 1-methyl-3-oxatricyclo[5.2.0.0 ]n onyl-2-acetic acid;

(0) decarboxylating and halogenating the acetic acid of step (b) to forml-methyl-4-halomethyl-3-oxatricyclo[5.2.0.0 ]nonane;

(d) cleaving the nonane of step (c) to form 9-hydroxyfi-pinene;

(e) tosylating the pinene of step (d) to form9-toluenesulfonyloxy-fl-pinene;

(f) displacing the pinene of step (e) with sodium diode to form9-iodo-fl-pinene;

(g) displacing the pinene of step (f) with lithium acetylide to form9-ethynyl-fi-pinene;

(h) hydroborating the pinene of step (g) with disiamylborane to form9-(fi-pinyl)-acetaldehyde; and

(i) reacting the aldehyde of step (h) with triphenylisopropylidenephosphorane to form cis-fi-bergamotene.

2. The process of claim 1 where in step (a) theZ-carboalkoxymethylnopinol and alkyl-l-methyl-3-oxatricycl0 [5.2.0.0n0nyl-2-acetate are respectively Z-carboethoxymethylnopinol and ethyll-methyl 3-oxatricyclo [5.2.0.0 ]nonyl-2-acetate.

3. The process of claim 1 where in step (c) the 1-methyl-4-halomethyl-3-oxatricyclo[5.2.0.0 ]nonane is 1-methyl-4-chloromethy1-3 -oxatricyclo [5.2.0.0 nonane.

References Cited H. C. Brown and G. Zweifel: The Hydroboration ofAcetylenes, Jacs 83 3834 (1961).

Fagerlund and Idler: Synthesis by the Wittig Reaction, lacs 79 6473(1961).

DELBERT E. GANTZ, Primary Examiner G. E. SCHMITKONS, Assistant ExaminerUS. Cl. X.R.

